Methods for the treatment of cognitive disorders

ABSTRACT

The invention relates to the use of certain compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT 3  receptors for the treatment of cognitive disorders such as attentional and memory deficits and dementia states.

This application is a division of application Ser. No. 07/424,736, filedOct. 20, 1989, now allowed, which is a division of application Ser. No.07/133,885, filed Dec. 16, 1987, now U.S. Pat. No. 4,985,437.

This invention relates to a new medical use for certain chemicalcompounds and pharmaceutical compositions containing them. In particularit relates to the use in the treatment of dementia and other cognitivedisorders of certain compounds which act as antagonists of5-hydroxytryptamine (5-HT) at receptors known in the art as 5-HT₃,5-HT`M` or 5-HT `M`-like` receptors. Such receptors have been describedfor example by Fozard et al., Eur. J. Pharmacol., 1979, 59, 195-210;Ireland, Straughan and Tyers, Br. J. Pharmacol., 1982, 75, 16P;Humphrey, Neuropharm., 1984, 23, 1503-1570; Richardson et al., Nature,1985, 316, 126-131; and Bradley et al., Neuropharm., 1986, 25, 563-576.Receptors of this type are now designated as 5-HT₃ receptors.

5-HT receptors of this type are located, for example, on the terminalsof afferent sensory neurones, in the isolated quinea-pig ileumpreparation and are also present in the central nervous system.Compounds which act as antagonists of 5-HT at 5-HT₃ receptors may beidentified using standard tests, for example, in vitro by measuringtheir inhibition of the depolarising effect of 5-HT on the rat or rabbitisolated vaqus nerve, or the tachycardia produced by 5-HT in the rabbitisolated heart or the contraction produced by 5-HT in the guinea-pigisolated ileum, or in vivo by measuring their effect on the VonBezold-Jarisch reflex (induced by 5-HT) as described, for example, inthe above-mentioned references.

A variety of compounds which act as antagonists of 5-HT at 5-HT₃receptors have been described in the art. Such compounds have beendisclosed inter alia in published UK Patent Applications Nos. 2100259,2125398, 2131420, 2132189, 2145416, 2152049, 2153821 and 2169292,published European Patent Applications Nos. 111608, 116255, 158265,191562, 200444, 210840, 214772, 219193, 221702, 226267, 227215, 230718,235878 and 242973, and published Australian Patent Application No.87/67121. The compounds disclosed in published European PatentApplication Nos. 13138, 67615, and 94742 have also been described asantagonists of 5-HT at 5-HT₃ receptors, in published European PatentApplications Nos. 215545 and 220011.

The compounds disclosed in these specifications have been described asbeing of use in a variety of conditions, including migraine.

We have now found that compounds which are disclosed in the abovespecifications and act as 5-HT antagonists at 5-HT₃ receptors are usefulin the treatment of cognitive disorders such as attentional and memorydeficits and dementia states. These types of condition occur in, forexample, senile dementia of the Alzheimers type, ageing, cerebrovasculardeficiency and Parkinson's disease.

Accordingly the invention provides a method of treatment of a subject,in particular a human subject, suffering from dementia or anothercognitive disorder, which comprises administering to the subject aneffective amount of a compound selected from compounds of formulae (I)to (VIII) as defined hereinafter or a physiologically acceptable salt orsolvate thereof.

The effectiveness of the compounds for use according to the presentinvention in the treatment of cognitive disorders may be demonstrated inrats in the spontaneous alternation test and in marmosets given learningtasks in the Wisconsin General Test Apparatus.

References in this specification to treatment include prophylactictreatment as well as the acute alleviation of symptoms.

Particular compounds for use in the present invention are those whichact as antagonists of 5-HT at 5-HT₃ receptors and are disclosed inpublished UK Patent Specifications Nos. 2100259, 2131420, 2132189,2145416, 2152049, 2153821 and 2169292, published European PatentSpecifications Nos. 13138, 67615, 111608, 116255, 158265, 191562,200444, 210840, 219193, 221702, 226267, 227215, 230718, 235878 and242973, published Australian Patent Application No. 87/67121, andcompounds of formula (I) as defined hereinafter. Compounds of formula(I) are described in UK Patent Specification No. 2125398.

Preferred compounds for use according to the invention are thosecompounds which act as antagonists of 5-HT at 5-HT₃ receptors describedin published UK Patent Specification Nos. 2100259, 2132189, 2152049 and2153821, published European Patent Specification Nos. 13138, 116255,200444, 221702, 226267, 235878 and 242973, published Australian PatentApplication No. 87/67121, and compounds of formula (I) as definedhereinafter.

Particularly preferred compounds for use according to the presentinvention are those described in published UK Patent Specification No.2100259, published European Patent Specification Nos. 200444 and 242973,and compounds of formula (I) as defined hereinafter.

A preferred group of compounds for use according to the invention,described in UK Specification No. 2125398, may be represented by thegeneral formula (I): ##STR1## wherein R₁ and R₂ independently representhydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, mercapto or C₁₋₄ alkylthio;

R₃ represents hydrogen, C₁₋₄ alkyl, C₃₋₅ alkenyl, aryl or aralkyl;

R₄ represents hydrogen, C₁₋₇ alkyl, C₃₋₅ alkenyl or aralkyl;

n is 2 or 3;

the free valence is attached to either fused ring, and the azabicyclicring is in either the exo or endo configuration; and acid addition saltsand quaternary ammonium salts thereof.

In the compounds of formula (I) R₁ and R₂ may, for example,independently represent hydrogen, halogen or C₁₋₄ alkyl, R₃ may be, forexample, hydrogen or C₁₋₄ alkyl and R₄ may be, for example, hydrogen,C₁₋₇ alkyl or aralkyl. The carbonyl group is preferably attached to the3-position of the indole ring. The azabicyclic ring is preferably in theendo configuration.

Another preferred group of compounds for use according to the invention,described in UK Specification No. 2100259, may be represented by thegeneral formula (II): ##STR2## wherein R₅ represents C₁₋₄ alkyl, C₁₋₄alkoxy, or halogen; and R₆ and R₇ independently represent hydrogen, C₁₋₄alkyl, C₁₋₄ alkoxy or halogen provided that R₆ is hydrogen when R₇ ishydrogen; and pharmaceutically acceptable salts thereof.

A preferred class of compounds of formula (II) are those in which R₅ andR₇ are the same and each represents methyl, methoxy or chlorine, and R₆represents hydrogen.

Yet another preferred group of compounds for use according to theinvention, described in European Specification No. 200444, may berepresented by the general formula (III): ##STR3## wherein Y is NH or 0;and p is 2 or 3;

and pharmaceutically acceptable salts thereof.

A further preferred group of compounds for use according to theinvention, described in UK Patent Specification No. 2153821 and EuropeanSpecifications Nos. 191562, 210840 and 219193, may be represented by thegeneral formula (IV): ##STR4## wherein R⁸ represents a hydrogen atom ora group selected from C₁₋₁₀ alkyl, C₃₋₆ alkenyl, C₃₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, phenyl or phenylC₁₋₃ alkyl, andin the case where Q represents a hydrogen atom, R⁸ may also represent--CO₂ R¹², --COR¹², --CONR¹² R¹³ or --SO₂ R¹² (wherein R¹² and R¹³,which may be the same or different, each represents a hydrogen atom, aC₁₋₆ alkyl or C₃₋₇ cycloalkyl group, or a phenyl or phenylC₁₋₄ alkylgroup, in which the phenyl group is optionally substituted by one ormore C₁₋₄ alkyl, C₁₋₄ alkoxy or hydroxy groups or halogen atoms, withthe proviso that R¹² does not represent a hydrogen atom when R⁸represents a group --CO₂ R¹² or --SO₂ R¹²);

one of the groups represented by R⁹, R¹⁰ and R¹¹ is a hydrogen atom or aC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, or phenylC₁₋₃ alkyl group,and each of the other two groups, which may be the same or different,represents a hydrogen atom or a C₁₋₆ alkyl group;

Q represents a hydrogen atom or a halogen atom or a hydroxy, C₁₋₄alkoxy, phenylC₁₋₃ alkoxy or C₁₋₆ alkyl group or a group --NR¹⁴ R¹⁵ or--CONR¹⁴ R¹⁵ (wherein R¹⁴ and R¹⁵, which may be the same or different,each represents ahydrogen atom or a C₁₋₄ alkyl or C₃₋₄ alkenyl group, ortogether with the nitrogen atom to which they are attached form asaturated 5 to 7 membered ring);

and physiologically acceptable salts and solvates thereof.

A preferred class of compounds represented by the formula (IV) for useaccording to the present invention is that wherein R⁸ represents ahydrogen atom or a methyl, ethyl, propyl, prop-2-yl, prop-2-enyl orcyclopentyl group; R¹⁰ represents a hydrogen atom; and either R⁹represents a methyl, ethyl, propyl or prop-2-yl group and R¹¹ representsa hydrogen atom or R⁹ represents a hydrogen atom and

R¹¹ represents a methyl or ethyl group; and Q represents a hydrogenatom.

A still further preferred group of compounds for use according to theinvention, described in European Patent Specification No. 242973, may berepresented by the general formula (V): ##STR5## wherein Im representsan imidazolyl group of formula: ##STR6## R¹⁶ represents a hydrogen atomor a C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, phenyl or phenylC₁₋₃ alkyl group;

R¹⁷ represents a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₇cycloalkyl, phenyl or phenylC₁₋₃ alkyl group;

R¹⁸ and R¹⁹, which may be the same or different, each represents ahydrogen atom or a C₁₋₆ alkyl group;

one of the groups represented by R²⁰, R²¹ and R²², is a hydrogen atom ora C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, phenyl or phenylC₁₋₃ alkylgroup, and each of the other two groups, which may be the same ordifferent, represents a hydrogen atom or a C₁₋₆ alkyl group; andphysiologically acceptable salts and solvates thereof.

A preferred class of compounds represented by the formula (V) for useaccording to the present invention are those wherein R¹⁶ represents ahydrogen atom or a methyl, prop-2-enyl or cyclopentyl group; R¹⁷represents a hydrogen atom or a methyl group; R¹⁸ and R¹⁹ eachindependently represent a hydrogen atom or a methyl group; R²⁰ and R²¹each represent a hydrogen atom; and R²² represents a hydrogen atom or aC₁₋₃ alkyl group, most preferably methyl.

Another preferred group of compounds for use according to the invention,described in European Specification No. 235878 and AustralianSpecification No. 87/67121, may be represented by the general formulae(VI) and (VII) respectively: ##STR7## wherein L is NH or O;

R²³ and R²⁴ are independently selected from hydrogen, halogen, CF₃, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₇ acyl, C₁₋₇ acylamino, C₁₋₆alkylsulphonylamino, N-(C₁₋₆ alkylsulphonyl)-N-C₁₋₄ alkylamino, C₁₋₆alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl,aminosulphonylamino or N-(aminosulphonyl)-C₁₋₄ alkylamino optionallyN-substituted by one or two groups selected from C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkylC₁₋₄ alkyl, phenyl or phenylC₁₋₄ alkyl groupsor optionally N-disubstituted by C₄₋₅ polymethylene;

Z is a moiety capable of hydrogen bonding to the NH group depicted informula (VI);

D and E are independently selected from hydrogen or C₁₋₄ alkyl, ortogether are a bond;

R²⁵ and R²⁶ are independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenylC₁₋₄ alkyl, or together are C₂₋₄ polymethylene;

M is a group of formula (a), (b) or (c): ##STR8## wherein t is 2 or 3; uis 1 or 2; v is 1 to 3; w is 1 to 3; and R²⁷ or R²⁸ is C₁₋₇ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkylC₁₋₂ alkyl or C₂₋₇ alkenylC₁₋₄ alkenyl;

and pharmaceutically acceptable salts thereof. A specific compoundwithin general formula (VII) as described in Example 5 of Australianspecification number 87/67121 isendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide.

Preferably L is NH; R²³ is often hydrogen and R²⁴ is hydrogen or a4-substituent such as halogen or methoxy; Z is preferably C--OCH₃,C--OC₂ H₅, C--OC₃ H₇, C--CO₂ CH₃, C--CO₂ C₂ H₅ or SO₂ N(CH₃)₂ ; often Dand E are both hydrogen; often R²⁵ and R²⁶ are both hydrogen; preferablyt is 2 or 3 and u, v and w are 1 or 2; and R²⁷ /R²⁸ is preferably methylor ethyl, most preferably methyl.

Yet another preferred group of compounds for use according to theinvention, described in UK Specification No. 2152049, may be representedby the general formula (VIII): ##STR9## wherein R¹, R² and R³ are asdefined for general formula (I) and G is a group of formula (d) or (e):##STR10## wherein R²⁹ is C₁₋₄ alkyl and R³⁰ is methoxy; andpharmaceutically acceptable salts thereof.

Particularly preferred compounds for use according to the presentinvention are (3α-tropanyl)-1H-indole-3-carboxylic acid ester andendo-N-(9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-methylindazole-3-carboxamideand physiologically acceptable salts and solvates thereof.

Other preferred compounds for use according to the present inventionare:

3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone;

1αH, 3α,5αH-tropan-3-yl-3,5-dimethylbenzoate; and physiologicallyacceptable salts and solvates thereof.

Further preferred compounds for use according to the present inventionare:

1αH, 3α,5αH-tropan-3-yl-3,5-dichlorobenzoate;indole-[5-(2-methyl-2-azabicyclo(2.2.2)octyl]-3-carboxylate;

1H-indol-3-yl-carboxylic acid (3R*, 4S*) -1-azabicyclo-[2.2.1]hept-3-ylester;

1H-indolyl-3-carboxylic acid 2S-(1-methyl-2-pyrrolidinylmethyl) ester;

4-amino-5-chloro-2-methoxy-N-(3-quinuclidinylmethyl)benzamide;1-methyl-3-indazolecarboxylic acid (endo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)ester;

(±)4-amino-5-chloro-2-methoxy-N-(6'α-[4'-thia-1'-azabicyclo[3,3,1]nonyl])benzamide;

(±)4-amino-5-chloro-2-methoxy-N-(6'α-]4'-oxa-1'-azabicyclo[3,3,1]nonyl])benzamide;

and physiologically acceptable salts and solvates thereof.

The invention also provides a pharmaceutical composition which comprisesan effective amount of at least one compound selected from compounds offormulae (I) to (VIII), for use in medicine, particularly humanmedicine, for the treatment of demential and other cognitive disorders.

In a further aspect the invention provides for the use of a compoundselected from compounds of formulae (I) to (VIII) for the manufacture ofa medicament for the treatment of dementia and other cognitivedisorders.

Pharmaceutical compositions for use according to the present inventionmay be formulated in conventional manner, optionally with one or morephysiologically acceptable carriers and/or excipients. For example, thecompounds described in the aforementioned patent specifications may beformulated in the manner described therein.

Compounds for use according to the present invention may be formulatedfor oral, buccal, parenteral, rectal or transdermal administration or ina form suitable for administration by inhalation or insufflation (eitherthrough the mouth or the nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

Compounds for use according to the present invention may be formulatedfor parenteral administration by injection e.g. by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form e.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds for use according to the present invention may also beformulated in rectal compositions such as suppositories or retentionenemas, e.g. containing conventional suppository bases such as cocoabutter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously,transcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compounds for use according to the presentinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The dose at which the compounds may be administered to man will dependupon the route of administration, the body weight of the patient, theseverity of the condition to be treated and the potency of thecompounds. For example, the compounds disclosed in the aforementionedpatent specifications may be administered at doses in the rangesspecified therein for the compounds, or at lower doses for example 0.5μg to 20 mg e.g. 0.005-20 mg, preferably 0.05-10 mg per unit dose whichmay be administered, for example, 1 to 4 times per day.

Thus a unit dose of a compound of formula (I) as herein defined maycontain from 0.2 to 250 mg of the active ingredient, and may beadministered for example up to four times per day, such that the overalldaily dose is in the range 0.5 to 500 mg.

A unit dose of a compound of formula (II) as herein defined may containfrom about 0.5 to 100 mg of the active ingredient, usually 1 to 50 mgand preferably 3 to 30 mg, and may be administered, for example, from 1to 4 times per day.

A unit dose of a compound of formula (III) as herein defined may contain0.5 to 1000 mg of the active ingredient, for example 1 to 500 mg, andmay be administered, for example, 1 to 4 times per day, such that thetotal daily dose is in the range 0.001 to 50 mg/kg, more usually 0.002to 25 mg/kg.

A unit dose of a compound of formula (IV) as herein defined may contain0.05 to 20 mg of the active ingredient, preferably 0.1 to 10 mg, and maybe administered 1 to 4 times per day.

A unit dose of a compound of formula (V) as herein defined may contain0.001 to 100 mg of the active ingredient, preferably 0.01 to 50 mg, andmay be administered 1 to 4 times per day.

A unit dose of a compound of formula (VI) as herein defined may contain0.05 to 1000 mg of the active ingredient, for example 0.1 to 500 mg, andmay be administered, for example, 1 to 4 times per day, such that thetotal daily dose is in the range 0.0001 to 50 mg/kg, more usually 0.0002to 25 mg/kg.

A unit dose of a compound of formula (VII) as herein defined may contain0.05 to 1000 mg of the active ingredient, for example 0.5 to 500 mg, andmay be administered, for example, 1 to 4 times per day, such that thetotal daily dose is in the range 0.0001 to 50 mg/kg, more usually 0.0002to 25 mg/kg.

A unit dose of a compound of formula (VIII) as herein defined maycontain from 0.1 to 250 mg of the active ingredient, and may beadministered up to four times per day, such that the overall daily doseis in the range 0.5 to 500 mg.

The following examples illustrate pharmaceutical formulations for useaccording to the invention, containing either(3α-tropanyl)-1H-indole-3-carboxylic acid ester or3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone asthe active ingredient. Other compounds for use according to theinvention may be formulated in a similar manner.

TABLETS FOR ORAL ADMINISTRATION

Tablets may be prepared by the normal methods such as direct compressionor wet granulation.

The tablets may be film coated with suitable film forming materials,such as hyroxypropyl methylcellulose, using standard techniques.Alternatively the tablets may be sugar coated.

Direct Compression Tablet

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        Active Ingredient     0.50                                                    Calcium Hydrogen Phosphate BP*                                                                      87.25                                                   Croscarmellose Sodium NF                                                                            1.8                                                     Magnesium Stearate BP 0.45                                                    Compression weiqht    90.0                                                    ______________________________________                                         *of a grade suitable for direct compression.                             

The active ingredient is passed through a 60 mesh sieve, blended withthe calcium hydrogen phosphate, croscarmellose sodium and magnesiumstearate. The resultant mix is compressed into tablets using a ManestyF3 tablet machine fitted with 5.5 mm, flat bevelled edge punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to excipients or the compression weight and usingpunches to suit.

CAPSULES

    ______________________________________                                                         mg/capsule                                                   ______________________________________                                        Active Ingredient  0.5                                                        *Starch 1500       98.5                                                       Magnesium Stearate BP                                                                            1.0                                                        Fill Weight        100.0                                                      ______________________________________                                         *a form of directly compressible starch.                                 

The active ingredient is sieved and blended with the excipients. The mixis filled into size No. 2 hard gelatin capsules using suitablemachinery. Other doses may be prepared by altering the fill weight andif necessary changing the capsule size to suit.

SYRUP

This may be either a sucrose or sucrose free presentation.

    ______________________________________                                                              mg/5 ml dose                                            ______________________________________                                        Sucrose-Free             0.5                                                  Active inqredient                                                             Hydroxypropylmethylcellulose USP                                                                      22.5                                                  (viscosity type 4000)                                                         Buffer                                                                        Flavour                                                                       Colour                      as required                                       Preservative                                                                  Sweetener                                                                     Purified Water BP to     5.0 ml                                               ______________________________________                                    

The hydroxypropylmethylcellulose is dispersed in hot water, cooled andthen mixed with an aqueous solution containing the active ingredient andthe other components of the formulation. The resultant solution isadjusted to volume and mixed. The syrup is clarified by filtration.

INJECTION FOR INTRAVENOUS ADMINISTRATION

    ______________________________________                                                        mg/ml                                                         ______________________________________                                        Active Ingredient 0.05        0.5                                             Sodium Chloride BP                                                                              as required as required                                     Water for Injection BP to                                                                       1.0 ml      1.0 ml                                          ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted, using acid or alkali, to that of optimumstability and/or facilitate solution of the active ingredient.Alternatively suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate sizeampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.Alternatively the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen or other suitable gas.

SUPPOSITORY

    ______________________________________                                        Active Ingredient      0.5 mg                                                 *Witepsol H15 to       1.0 g                                                  ______________________________________                                         *Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur.           

A suspension of the active ingredient is prepared in the molten Witepsoland filled, using suitable machinery, into 1 g size suppository moulds.

The efficacy of the compounds for use according to the invention in thetreatment of cognitive disorders has been demonstrated in marmosetsgiven learning tasks in the Wisconsin General Test Apparatus.

Test compounds:

(3α-Tropanyl)-1H-indole-3-carboxylic acid ester and3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone.

Marmoset learning tasks in the Wisconsin General Test Apparatus

Introduction and Test Procedure

Common marmosets were tested for performance in a discriminativelearning task and reverse learning task using the Wisconsin General Testapparatus described by Harlow H. F., Psychological Review, 56, 51-65,1949. The experiments were essentially carried out following theexperimental protocol of Baker H. F., Ridley R. M. and Drewett, B.,Psychopharmacology, 91, 512-514, 1987. The test compound wasadministered into the hind leg of the marmoset as a subcutaneous (s.c)injection in 1 ml of saline.

Results

Administration of either of the test compounds at a dose of 10 ng/kgs.c. twice a day throughout testing improved the performance of themarmosets in the reverse learning task.

I claim:
 1. A method of improving cognition in a patient suffering fromdementia or other cognitive disorder which comprises administering tothe patient an effective amount ofendo-N-(8-methyl-8-azabicyclooct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide,or a physiologically acceptable salt or solvate thereof, which compoundacts as a 5-HT antagonist at 5-HT₃ receptors.